1) Field of the Invention
The present invention relates to vehicles and methods for improving nerve regeneration after nerve injury.
2) Description of Related Art
“Peripheral nerve” is a term used synonymously to describe the peripheral nervous system. The peripheral nervous system is a network of motor and sensory nerves that connect the brain and spinal cord (the central nervous system or CNS) to the entire human body. These nerves control the functions of sensation, movement and motor coordination. The peripheral nerves are a complicated, extensive network of nerves that are the tool for the brain and spinal cord to communicate with the rest of the body. They are fragile and can be damaged easily. Trauma, including battlefield injuries, is a major cause of peripheral nerve injury along with birth trauma (brachial plexus injury) and injuries related to surgeries. Limited data is available to determine the incidence of peripheral nerve injury.
Neurons, nerve cells that are the basic building block of the nervous system, generate their own proteins within cytoplasmic processes that extend for centimeters in rodents and more than a meter in humans. These locally generated proteins are needed for regeneration after nerve injury. Protein synthesis in axons contributes to axon growth during development and regeneration.
The stress response in eukaryotic cells often inhibits translation initiation and leads to the formation of cytoplasmic RNA-protein complexes referred to as stress granules. Stress granules, dense aggregations in the cytosol (the aqueous component of the cytoplasm of a cell) comprised of proteins and RNAs, are used to store mRNAs during periods of cellular stress, but nerve injury with compromise of axon integrity paradoxically causes stress granules to disaggregate presumably releasing mRNAs for translation. Stress granules contain non-translating mRNAs, translation initiation components, and many additional proteins affecting mRNA function. Stress granules have been proposed to affect mRNA translation and stability, as well as being linked to apoptosis and nuclear processes. Stress granules also interact with P-bodies, another cytoplasmic RNP granule containing non-translating mRNA, translation repressors and some mRNA degradation machinery. Together, stress granules and P-bodies reveal a dynamic cycle of distinct biochemical and mRNA-protein complexes (mRNPs) in the cytosol, with implications for the control of mRNA function.
Nerve regeneration is abysmally slow in the peripheral nervous system and does not occur spontaneously in the central nervous system. Despite that regeneration occurs in the periphery, the slow growth in humans means that by the time regeneration occurs the distal nerve is no longer a growth-supportive environment and the target tissues are no longer receptive for reinnervation that restores the nerve supply to a part of the body. There is a pressing clinical need for treatments that will accelerate axon regeneration in peripheral nerves.
Regeneration in the brain and spinal cord is thought to fail because of extrinsic inhibitors of axon growth and the low intrinsic growth potential of central nervous system neurons. Some approaches to increase intrinsic growth potential of neurons have been shown to also overcome the extrinsic growth inhibitors. There is a pressing clinical need for better agents to increase intrinsic growth that directly target the axons.
Current products in use clinically consist of a myriad of ‘gap bridging’ approaches for peripheral nerve treatments. Experimentally, these have been encapsulated with various growth promoting agents (e.g., growth factors), but none have specifically targeted regeneration rates. Other approaches include exercise, which is used clinically for rehabilitation/physical therapy, but likely has some regenerative effects. For both stroke and spinal cord injury, rehabilitation is similarly used in clinics. Experimental evidence points to some enhanced regeneration with these techniques.
Accordingly, it is an object of the present invention to provide vehicles and methods for improving nerve regeneration after nerve injury.